A major advance in our understanding of acid-base homeostasis and ammonia metabolism is the identification that Rh glycoproteins are ammonia transporters. In the kidney, multiple lines of evidence suggest that Rh glycoprotein C Glycoprotein (Rhcg) is critically important in renal ammonia metabolism. A second advance has been the recognition that Rhcg is expressed in principal cells, a cell not generally known to be involved in acid-base homeostasis, and that principal cell Rhcg expression parallels ammonia excretion. Thus, principal cells may contribute to regulated transcellular ammonia secretion. Finally, Rhcg expression appears to be regulated through post-transcriptional mechanisms. The overall aim of this application is to determine the roles of Rhcg in acid-base homeostasis and the molecular mechanisms underlying Rhcg-mediated ion transport and posttranscriptional Rhcg regulation. The first goal is to determine the specific role of Rhcg in intercalated cell-mediated ammonia metabolism. We will use Cre-loxP technology to generate intercalated cell-specific Rhcg knockout mice, which we will use to determine the role of intercalated cell Rhcg in normal acid-base homeostasis, and in the renal response to chronic metabolic acidosis and hypokalemia. Our second aim is to determine the role of Rhcg in principal cell-mediated ammonia secretion. We will generate principal cell-specific Rhcg knockout mice and will use these mice to determine the role of principal cell Rhcg in basal acid-base homeostasis and in the renal response to metabolic acidosis and hypokalemia.